Cinacalcet failure raises trial conduct issues

The oral calcimimetic agent, cinacalcet, has been found to have no significant effect on cardiovascular (CV) events or death in patients with chronic kidney disease in a randomized controlled trial.

However, unanticipated baseline characteristics and high crossover rates resulted in reduced power to properly test the drug's effects, say investigators Glen Chertow (Stanford University School of Medicine, California, USA) and colleagues.

"The real insights from this study are for clinical trialists and regulators," say Vlado Perkovic and Bruce Neal (University of Sydney, Australia) in an accompanying editorial. "We need to change the way we study the effects of new drugs and integrate these changes into regulatory processes, guideline development, and clinical practice."

The Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial showed a nonsignificant 7% reduction in risk for death or major CV events among patients with end-stage renal disease who received cinacalcet compared with those who received placebo.

Of 3883 patients who were randomly allocated to a mean daily dose of either 55 mg cinacalcet over a median 21.2 months or placebo over 17.5 months, 48.2% in the cinacalcet group and 49.2% in the placebo group died, had a myocardial infarction, or were hospitalized for unstable angina, heart failure, or a peripheral vascular event.

Although this represented a nonsignificant 7% reduction in risk for death or nonfatal CV events in the cinacalcet versus placebo group, the authors report that adjustment for baseline characteristics led to a nominally significant 12% reduction.

"We could not have anticipated the observed baseline imbalances between randomized groups, including a 1-year difference in age, the most potent predictor of death or cardiovascular events, which materially influenced the relative hazard and level of significance," says the team.

Futhermore, there were high rates of treatment crossover during the trial with almost two-thirds of patients in the cinacalcet group discontinuing active therapy, and one-fifth of placebo patients switching to cinacalcet before trial completion.

However, Perkovic and Neal suggest that if changes can be made to the way the effects of new drugs are studied and integrated into regulatory processes and guidelines, then "even a negative result from the EVOLVE trial will have had a very positive effect."

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